Neo-Adjuvant Use of Sorafenib for Hepatocellular Carcinoma Awaiting Liver Transplantation.

Data on efficacy and safety of sorafenib in a neoadjuvant setting for HCC awaiting liver transplantation (LT) are heterogeneous and scarce. We aimed to investigate the trajectory of patients treated with sorafenib while awaiting LT. All patients listed for HCC and treated with sorafenib were included in a monocentric observational study. A clinical and biological evaluation was performed every month. Radiological tumor response evaluation was realized every 3 months on the waiting list and every 6 months after LT. Among 327 patients listed for HCC, 62 (19%) were treated with Sorafenib. Sorafenib was initiated for HCC progression after loco-regional therapy (LRT) in 50% of cases and for impossibility of LRT in 50% of cases. The mean duration of treatment was 6 months. Thirty six patients (58%) dropped-out for tumor progression and 26 (42%) patients were transplanted. The 5-year overall and recurrent-free survival after LT was 77% and 48% respectively. Patients treated for impossibility of LRT had acceptable 5-year intention-to-treat overall and post-LT survivals. Conversely, patients treated for HCC progression presented high dropout rate and low intention-to-treat survival. Our results suggest that it is very questionable in terms of utility that patients treated for HCC progression should even be kept listed once the tumor progression has been observed.

Efficacy and safety of boceprevir-based triple therapy in HCV cirrhotic patients awaiting liver transplantation (ANRS HC29 BOCEPRETRANSPLANT).

BACKGROUND AND AIMS: In this French multicentre, open-label study, we analyzed the efficacy, safety and patient-reported outcomes of a boceprevir-based triple therapy in HCV genotype 1 cirrhotic patients awaiting liver transplantation (LT). METHODS: Patients received PEG-IFN/ribavirin (RBV) for 48 weeks (W) and boceprevir from W4 to W48 or until LT. RESULTS: Fifty-one patients (80% males, median age: 56 years) were included. Fifty-seven percent had hepatocellular carcinoma and 43% end-stage liver disease. At enrolment, the median MELD score was 9 (range: 6-18); the Child-Pugh score was A in 65%, B in 35% and C in 2%. Therapy was discontinued because of severe adverse events (SAEs) in 39% of cases and virological inefficacy in 24%. 16% of patients had undetectable HCV RNA 24 weeks after the end of treatment (SVR24). LT was performed in 18 patients (35%). HCV RNA was undetectable in 16.6% at LT. Seven patients (14%) died and three deaths were attributed to treatment. SAEs (n=129) were observed in 84% of patients. Twenty-four percent of patients developed severe infections. Albumin<35g/L was independently associated with severe infection. Compared with baseline values, a significant decrease (P=0.02) of the physical dimension of health-related quality of life was observed between W4 and W24. The mean (95% CI) number of self-reported symptoms doubled during treatment (from 6.3 [4.8-7.7] to 11.8 [9.3-14.3]; P<0.001). CONCLUSIONS: The safety of the PEG-IFN/RBV/boceprevir combination is poor in patients awaiting LT, with a high risk of severe infection. Moreover, the limited efficacy confirms the indication for IFN-free combinations in these patients.

Sofosbuvir-based treatment of hepatitis C with severe fibrosis (METAVIR F3/F4) after liver transplantation.

Recurrence of hepatitis C virus (HCV) after liver transplantation (LT) can rapidly lead to liver graft cirrhosis and, therefore, graft failure and retransplantation or death. The aim of the present study was to assess efficacy and tolerance of sofosbuvir (SOF)-based regimens for the treatment of HCV recurrence in patients with severe fibrosis after LT. The Compassionate Use of Protease Inhibitors in Viral C Liver Transplantation (CULPIT) study is a prospective multicenter cohort including patients with HCV recurrence following LT treated with second generation direct antivirals. The present study focused on patients included between October 2013 and November 2014 and diagnosed with HCV recurrence and liver graft extensive fibrosis (METAVIR F3/F4). A SOF-based regimen was administered to 125 patients fulfilling inclusion criteria. The median delay from LT was 95.9 ± 69.6 months. The characteristics of patients were as follows: mean age, 59.4 ± 9.0 years; 78.4% male; infected by HCV genotype 1: 78.2%, mean HCV RNA: 6.1 ± 1.0 log10 IU/mL. Eighty patients had failed previous post-LT antiviral therapy (64.0%) including triple therapy with first generation protease inhibitors in 19 (15.2%) patients. The main combination regimen was SOF/daclatasvir (73.6%). Ribavirin was used in 60 patients. Sustained virological response 12 weeks after treatment was 92.8% (on an intention-to-treat basis); 7 patients with virological failure were observed. Serious adverse events occurred in 25.6% of the patients during antiviral treatment. During antiviral treatment and follow-up, 3 patients were retransplanted and 4 patients died. In conclusion, SOF-based antiviral treatment shows very promising results in patients with HCV recurrence and severe fibrosis after LT. Liver Transplantation 22 1367-1378 2016 AASLD.

Drug-Eluting Beads Loaded With Doxorubicin (DEBDOX) Chemoembolisation Before Liver Transplantation for Hepatocellular Carcinoma: An Imaging/Histologic Correlation Study.

PURPOSE: Most transplant centers use chemoembolisation as locoregional bridge therapy for hepatocellular carcinoma (HCC) before liver transplantation (LT). Chemoembolisation using beads loaded with doxorubicin (DEBDOX) is a promising technique that enables delivery of a large quantity of drugs against HCC. We sought to assess the imaging-histologic correlation after DEBDOX chemoembolisation. MATERIALS AND METHODS: All consecutive patients who had undergone DEBDOX chemoembolisation before receiving liver graft for HCC were included. Tumour response was evaluated according to Response Evaluation Criteria in Solid Tumours (RECIST) and modified RECIST (mRECIST) criteria. The result of final imaging made before LT was correlated with histological data to predict tumour necrosis. RESULTS: Twenty-eight patients underwent 43 DEBDOX procedures for 45 HCC. Therapy had a significant effect as shown by a decrease in the mean size of the largest nodule (p = 0.02) and the sum of viable part of tumour sizes according to mRECIST criteria (p < 0.001). An objective response using mRECIST criteria was significantly correlated with mean tumour necrosis ≥90 % (p = 0.03). A complete response using mRECIST criteria enabled accurate prediction of complete tumour necrosis (p = 0.01). Correlations using RECIST criteria were not significant. CONCLUSION: Our data confirm the potential benefit of DEBDOX chemoembolisation as bridge therapy before LT, and they provide a rational basis for new studies focusing on recurrence-free survival after LT. Radiologic evaluation according to mRECIST criteria enables accurate prediction of tumour necrosis, whereas RECIST criteria do not.

Is expert opinion reliable when estimating transition probabilities? The case of HCV-related cirrhosis in Egypt.

BACKGROUND: Data on HCV-related cirrhosis progression are scarce in developing countries in general, and in Egypt in particular. The objective of this study was to estimate the probability of death and transition between different health stages of HCV (compensated cirrhosis, decompensated cirrhosis and hepatocellular carcinoma) for an Egyptian population of patients with HCV-related cirrhosis. METHODS: We used the "elicitation of expert opinions" method to obtain collective knowledge from a panel of 23 Egyptian experts (among whom 17 were hepatologists or gastroenterologists and 2 were infectiologists). The questionnaire was based on virtual medical cases and asked the experts to assess probability of death or probability of various cirrhosis complications. The design was a Delphi study: we attempted to obtain a consensus between experts via a series of questionnaires interspersed with group response feedback. RESULTS: We found substantial disparity between experts' answers, and no consensus was reached at the end of the process. Moreover, we obtained high death probability and high risk of hepatocellular carcinoma. The annual transition probability to death was estimated at between 10.1% and 61.5% and the annual probability of occurrence of hepatocellular carcinoma was estimated at between 16.8% and 58.9% (depending on age, gender, time spent in cirrhosis and cirrhosis severity). CONCLUSIONS: Our results show that eliciting expert opinions is not suited for determining the natural history of diseases due to practitioners' difficulties in evaluating quantities. Cognitive bias occurring during this type of study might explain our results.

Impact of emerging hepatitis C virus treatments on future needs for liver transplantation in France: a modelling approach.

BACKGROUND: In light of the impact of emerging hepatitis C virus treatments on morbidity and mortality, we sought to determine whether candidates for liver transplantation for hepatocellular carcinoma and decompensated cirrhosis will decrease sufficiently to match liver grafts for hepatitis C virus-infected patients. AIMS: Using a Markov model, we quantified future liver graft needs for hepatitis C virus-induced diseases and estimated the impact of current and emerging treatments. METHODS: We simulated progression of yearly-hepatitis-C-virus-infected cohorts from the beginning of the epidemic and calculated 2013-2022 candidates for liver transplantation up until 2022 without and with therapies. We compared these estimated numbers to projected trends in liver grafts for hepatitis C virus. RESULTS: Overall, current treatment would avoid transplantation of 4425 (4183-4684) potential candidates during the period 2013-2022. It would enable an 88% and 42% reduction in the gap between liver transplantation activity and candidates for hepatocellular carcinoma and decompensated cirrhosis, respectively. Emerging hepatitis C virus treatments would allow adequacy in transplant activities for hepatocellular carcinoma. However, they would not lead to adequacy in decompensated cirrhosis from 2013 to 2022. Results were robust to sensitivity analysis. CONCLUSION: Our study indicates that patients will benefit from public health policies regarding hepatitis C virus screening and therapeutic access to new emerging treatments.

Assessing bone status in patients awaiting liver transplantation.

UNLABELLED: Osteoporosis is common in liver transplant recipients as a result of both iatrogenic factors and preexisting hepatic osteodystrophy. OBJECTIVES: To assess the prevalences of osteoporosis and fractures and to identify risk factors for these two abnormalities in patients awaiting liver transplantation for end-stage liver disease. METHODS: Between January 2006 and December 2007, patients on a liver transplant waiting list underwent a routine evaluation comprising the identification of risk factors for osteoporosis, radiographs of the spine, bone mineral density measurements (BMD), and laboratory tests (phosphate and calcium levels, hormone assays, liver function tests, and bone turnover markers). RESULTS: We studied 99 patients (70 males and 20 females; mean age, 55 ± 8 years) including 75% with alcohol-induced cirrhosis with or without hepatocarcinoma. Among them, 36% had radiographic vertebral fractures, 38% had osteoporosis, 35% had osteopenia, and 88% had vitamin D insufficiency or deficiency (25(OH)vitamin D3<20 ng/mL). Lower BMD values were associated with vertebral fractures; the odds ratios and 95% confidence intervals for each BMD decrease of 1 SD were as follows: spine, 1.45 (95%CI, 1.1-1.9); total hip, 2.1 (95%CI, 1.3-3.2); and femoral neck, 2 (95%CI, 1.3-3.1) (P<0.05). Levels of bone resorption markers correlated negatively with BMD at the spine and hip. The Model for End-Stage Liver Disease score correlated negatively with hip BMD. CONCLUSION: Our findings suggest high prevalences of low BMD values and vertebral fractures among patients awaiting liver transplantation. Bone status should be evaluated routinely in candidates to liver transplantation.

Primary sarcoma of the liver and transplantation: a case study and literature review.

Primary sarcomas of the liver are rare tumors and their diagnosis is difficult to assess, particularly on percutaneous liver biopsy. Epithelioid hemangioendothelioma (EHE) is an infrequent indication for liver transplantation, and angiosarcoma (AS) is a widely recognized contraindication because of its poor prognosis. We report the case of a young woman who underwent liver transplantation (LT) for an infiltrative hepatic tumor with several features suggestive of EHE, although the analysis of the native liver revealed AS. Everolimus was used as the main immunosuppressive drug. More than two years after LT, her physical condition remained stable despite a local recurrence at 10 months. In this setting, the ranking of new immunosuppressive agents belonging to the family of the proliferation signal inhibitors will need to be precise, but their intrinsic properties suggest a potential use in treatments after LT for atypical malignancies.

Impact of impaired aerobic capacity on liver transplant candidates.

BACKGROUND: Oxygen consumption at peak exercise (peak VO2) is the most accurate index of aerobic capacity (AC), which reflects the physical condition of an individual and is currently considered the gold standard for cardiorespiratory fitness. Evaluation of peak VO2 to identify high-risk candidates for liver transplantation (LT) may represent an interesting approach. The aims of this study were (a) to describe AC and identify factors independently associated with peak VO2; (b) to analyze the prognostic value of peak VO2 in patients referred for preliminary evaluation of LT; and (c) to provide preliminary data on the influence of peak VO2 on length of hospitalization and the need for oxygen support after LT. RESULTS: Peak VO2 was determined in patients referred for preliminary evaluation for LT. One hundred thirty-five candidates were included. More than half had severe alterations in peak VO2. Age, gender, model-for-end-stage liver disease (MELD) score, tobacco use, and hemoglobin were independently associated with peak VO2. Candidates with severe alterations in peak VO2 had a lower 1-year survival than others. Model-for-end-stage liver disease score and peak VO2 were independently associated with survival. In patients with a MELD above 17, those with severe alterations of peak VO2 AC had lower 1-year survival than the others. Among patients who underwent LT, those with severe impairment of peak VO2 showed a trend toward a higher mean length of hospitalization after LT and had significantly longer need for oxygen support. CONCLUSIONS: Peak VO2 is severely impaired in candidates for LT and affects survival and post-LT course. Perioperative respiratory rehabilitation programs validated in lung and heart transplantation must be tested.

Impact of viral eradication on mortality related to hepatitis C: a modeling approach in France.

BACKGROUND/AIMS: In France, two recent studies enabled modeling of the impact of viral eradication on HCV mortality. METHODS: The French HCV population was simulated from infection to death using a computer-based model. We took into account the impact of alcohol, present screening and antiviral therapy to predict 2006--2025 HCV mortality and to assess the impact of viral eradication. RESULTS: In 2006, the model estimated that among HCV-RNA+, 55% were F0-F1, 18% F2, 22% F3-F4 and 6% had liver complications. The mortality ratio was 11-fold higher in alcoholic patients 40-65 years old. Current therapy will save 14,400 (95% CI, 13,900-15,000) lives compared to absence of therapy. Sensitivity analyses did not change the main results. Contrary to guidelines, if patients F<2 were treated in the same proportions as those with F> or = 2,700 (95% CI, 700-750) lives would be saved. If screening were to reach 75% in 2010, 4 years earlier than model expectation, 950 (95% CI, 900-1000) lives would be saved. If a new molecule improving eradication for genotype 1/4 by 40% were to become available in 2010, 1500 (95% CI, 1400-1600) lives would be saved. CONCLUSIONS: Current therapy is reducing HCV mortality. Therapeutic guidelines must take into account their impact on HCV mortality.

Comparison of two techniques of transarterial chemoembolization before liver transplantation for hepatocellular carcinoma: a case-control study.

Supraselective transarterial chemoembolization (STACE) more efficiently targets chemotherapy delivered via the feeding arterial branches of the tumor than does conventional transarterial chemoembolization (TACE). However, the hypothesis of its greater efficacy compared with the latter is subject to controversy. The aim of the present study was to compare STACE to conventional TACE in a controlled study of candidates for liver transplantation (LT) for hepatocellular carcinoma (HCC). Patients were matched for factors associated with HCC recurrence and survival. Sixty patients were included: 30 who were treated with STACE and 30 treated with conventional TACE. The 2 groups were similar in terms of matched criteria. In the overall population (uni- and multinodular HCC), there was no marked difference between the 2 groups in 5-year disease-free survival: 76.8% vs. 74.8%. In sensitivity analysis of patients considered to be the best candidates for TACE (uninodular HCC < or =5 cm), there was a trend toward significance between STACE and TACE in 5-year disease-free survival: 87% vs. 64% (P = 0.09). The only factor associated with complete tumor necrosis was STACE in the overall population (30.8% vs. 6.9%, P = 0.02), with a similar trend in the subgroup of patients with a single nodule (33.3% vs. 6.7%, P = 0.06), whereas the mean number of procedures was similar in the 2 groups (mean, 1.3 procedures; range 1-5 procedures; P = NS). STACE is more efficient at inducing complete tumor necrosis in the liver. This study observed trends toward improvement in the disease-free survival of patients with uninodular HCC < or =5 cm. Future studies focusing on such patients are warranted.

Conversion to sirolimus: a useful strategy for recalcitrant cutaneous viral warts in liver transplant recipient.

Dermatological complications following transplantation are very common and the majority of immunosuppressed transplant recipients develop some to many warts due to human papillomavirus (HPV) infection. In the setting of immunosuppression, therapeutic management may be disappointing because of the extent of the lesions in patients unable to develop a sufficient immune response directed against HPV. We report here a case of a young liver transplant recipient who developed diffuse recalcitrant HPV-induced warts leading to an impairment of her quality of life. Taking into account the antiproliferative and cytostatic properties of the target-of-rapamycin (TOR) inhibitors, a new class of immunosuppressive drug, we significantly modified the immunosuppressive regimen. Conversion to sirolimus was followed by a rapid improvement of cutaneous state suggesting that this strategy may be useful for recalcitrant cutaneous viral warts in transplant recipient.

Impaired expression of the peroxisome proliferator-activated receptor alpha during hepatitis C virus infection.

BACKGROUND AND AIMS: Liver inflammation, fibrosis, and dyslipidemia are common features in patients with chronic hepatitis C virus (HCV) infection. Because peroxisome proliferator-activated receptor alpha (PPARalpha) is highly expressed in the liver and is involved in the regulation of lipid metabolism and inflammation, we sought to determine whether HCV infection may locally impair PPARalpha expression and activity. METHODS: PPARalpha expression was investigated in liver biopsy specimens of 86 untreated patients with HCV infection and controls, by using real-time polymerase chain reaction (PCR), Western blot analysis, and immunohistochemistry. PPARalpha activity was assessed by quantification of the key gene target carnitine palmitoyl acyl-CoA transferase 1 (CPT1A) messenger RNA (mRNA). The influence of HCV core protein on PPARalpha mRNA expression was analyzed in vitro by real-time PCR in HCV core-expressing HepG2 cells activated with the PPARalpha ligand fenofibric acid. RESULTS: Hepatic concentrations of PPARalpha and CPT1A expressed by hepatocytes were impaired profoundly in the livers of untreated patients with HCV infection compared with controls. A mean decrease of 85% in PPARalpha mRNA expression paralleled with a lack of CPT1A mRNA induction also were observed in HCV core-expressing HepG2 cells compared with controls. CONCLUSIONS: HCV infection is related to altered expression and function of the anti-inflammatory nuclear receptor PPARalpha. These results identify hepatic PPARalpha as one mechanism underlying the pathogenesis of HCV infection, and as a new therapeutic target in traditional treatment of HCV-induced liver injury.

Daily or three times a week interferon alfa-2b in combination with ribavirin or interferon alone for the treatment of patients with chronic hepatitis C.

BACKGROUND/AIMS: Data on hepatitis C virus (HCV) viral dynamics and on the effect of interferon in blocking virion production have suggested a rationale for daily administration of interferon in patients with chronic hepatitis C infection. We compared the efficacy and safety of daily interferon alfa-2b in combination with ribavirin with those of interferon alfa-2b three times a week alone or in combination with ribavirin. METHODS: We randomly assigned 321 patients with chronic hepatitis C to receive standard-dose interferon alfa-2b alone or in combination with ribavirin for 48 weeks or daily interferon alfa-2b (3 million units per day for 12 weeks then 3 million units three times per week for 24 weeks) and ribavirin (36 week treatment). RESULTS: The rate of sustained virologic response (defined as an undetectable serum HCV-RNA level 72 weeks after initiation of treatment) was higher in patients who received combination therapy with three times weekly interferon (51.7%) or daily interferon (46.1%) than in patients who received interferon alone (25%) (P=0.0001 and P=0.002, respectively). Independent predictive factors for sustained virologic response were combination therapy, weight, genotype and viral load. In conclusion, in patients with chronic hepatitis C, combination therapy with induction treatment (daily interferon for 12 weeks) and shorter duration of treatment was not different from combination therapy for 48 weeks without induction treatment. CONCLUSIONS: Induction treatment with interferon for 12 weeks and combination therapy for a total duration of 36 weeks could therefore be cost effective.